H.C. Kluin-Nelemanshttp://repub.eur.nl/ppl/13390/
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RePub, Erasmus University RepositoryAn in vitro model for cytogenetic conversion in CML. Interferon-alpha preferentially inhibits the outgrowth of malignant stem cells preserved in long-term culturehttp://repub.eur.nl/pub/8894/
Thu, 01 Jan 1998 00:00:01 GMT<div>J.J. Cornelissen</div><div>R.E. Ploemacher</div><div>B.W. Wognum</div><div>A. Borsboom</div><div>H.C. Kluin-Nelemans</div><div>A. Hagemeijer</div><div>B. Löwenberg</div>
IFN-alpha has been shown to prolong survival in chronic myeloid leukemia
patients, but its mechanism of action is still not understood. The human
cobblestone area-forming cell (CAFC) assay allows for the measurement of
the concentration of normal as well as malignant stem cells, while their
progeny can be measured in parallel long-term culture (LTC) in flasks.
Using CAFC and LTC assays, we have examined direct effects of IFN-alpha
(500; 5,000 IU/ml) on the maintenance and outgrowth of CD34-enriched
normal and malignant stem cells, obtained from six patients with an
established major cytogenetic response to IFN-alpha and from four
nonresponding patients. CAFC concentrations were not affected by
IFN-alpha. In contrast, IFN-alpha strongly inhibited the clonogenic output
in flask LTC. Nucleated cells (NC) produced in LTC were evaluated by
fluorescent in situ hybridization (FISH) for the presence of the
Philadelphia (Ph) translocation. After 8 wk of LTC, the percentage of Ph+
NCs produced was significantly more inhibited by IFN-alpha in responding
patients than in nonresponders. Control LTC without IFN-alpha showed no
significant differences of Ph+ NC production between responders and
nonresponders. These findings provide the first in vitro model for
cytogenetic conversion and suggest that direct antiproliferative effects
of IFN-alpha account for the cytogenetic response observed clinically.